Targeted Nanomedicines with Synergistic Chemotherapeutics to Enhance Immunotherapy of Metastatic Colorectal Cancer

项目摘要 结直肠癌（CRC）是美国癌症相关死亡的第二大原因。 超过一半的CRC患者在诊断时有区域或远处转移， 那些转移到其他器官的患者的5年生存率仅为~ 12%。检查点 阻断免疫疗法刺激宿主免疫系统产生抗肿瘤免疫 反应，并已显示出令人印象深刻的结果，治疗患者与错配修复（MMR） CRC缺陷。然而，高达95%的转移性CRC（mCRC）患者患有MMR- 熟练的，微卫星稳定的疾病，谁不受益于目前的免疫疗法。我们 建议开发基于纳米配位聚合物的靶向纳米药物， 奥沙利铂和双氢青蒿素（DHA），两种免疫原性化疗剂，用于治疗 mCRC。EGFR靶向纳米药物可以对CRC细胞产生直接的细胞毒性作用， 同时诱导和增强抗肿瘤免疫作用。我们提议下列 具体目的是为了开发一种新的联合化疗纳米药物和 检查点阻断免疫疗法用于有效治疗mCRC。 目的1：探讨OxPt/DHA纳米粒对结直肠癌细胞的抗癌作用机制。 目的2：用抗EGFR Fab将OxPt/DHA纳米颗粒主动靶向CRC。 目的3：评价OxPt/DHA和EGFR-OxPt/DHA纳米颗粒在小鼠中的抗癌功效。 CRC的原位小鼠模型。 目的4：阐明OxPt/DHA抗肿瘤的免疫机制 或EGFR-OxPt/DHA纳米颗粒与PD-L1抗体的组合。 通过这些目标，我们寻求建立一种新的治疗mCRC的模式， 提高mCRC免疫治疗的应答率和治疗效果。鉴于 检查点阻断免疫疗法已被FDA批准用于治疗多种类型的 癌症，我们利用化疗纳米药物作为免疫系统助推器的策略 加强检查点阻断对治疗其他转移性癌症具有广泛的影响。

Project Summary Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Over half of CRC patients have regional or distant metastasis at the time of diagnosis, and those with metastases to other organs have a 5-year survival rate of only ~12%. Checkpoint blockade immunotherapy stimulates the host immune system to generate an antitumor immune response, and has showed impressive results treating patients with mismatch repair (MMR) deficient CRC. However, up to 95% of patients with metastatic CRC (mCRC) have MMR- proficient, microsatellite-stable disease, who do not benefit from current immunotherapy. We propose to develop nanoscale coordination polymer-based targeted nanomedicines containing oxaliplatin and dihydroartemesinin (DHA), two immunogenic chemotherapeutics, for treating mCRC. EGFR-targeted nanomedicines can exert direct cytotoxic effects on CRC cells, and simultaneously induce and potentiate an antitumor immune effect. We propose the following Specific Aims in order to develop a novel combined chemotherapeutic nanomedicine and checkpoint blockade immunotherapy for the effective treatment of mCRC. Aim 1: Evaluate the mechanisms of OxPt/DHA nanoparticle anticancer efficacy on CRC cells. Aim 2: Actively target OxPt/DHA nanoparticles to CRC with an anti-EGFR Fab. Aim 3: Evaluate the anticancer efficacy of OxPt/DHA and EGFR-OxPt/DHA nanoparticles in orthotopic mouse models of CRC. Aim 4: Elucidate the immune mechanisms of antitumor response in mice treated with OxPt/DHA or EGFR-OxPt/DHA nanoparticles in combination with PD-L1 antibody. Through these aims, we seek to establish a new paradigm for the treatment of mCRC by increasing the response rate and therapeutic efficacy of immunotherapy for mCRC. Given that checkpoint blockade immunotherapies have been approved by FDA to treat multiple types of cancers, our strategy of utilizing chemotherapeutic nanomedicine as an immune system booster to potentiate checkpoint blockade can have broad impact on treating other metastatic cancers.